scholarly journals The Role of Constitutive Androstane Receptor in Oxazaphosphorine-Mediated Induction of Drug-Metabolizing Enzymes in Human Hepatocytes

2011 ◽  
Vol 28 (8) ◽  
pp. 2034-2044 ◽  
Author(s):  
Duan Wang ◽  
Linhao Li ◽  
Jennifer Fuhrman ◽  
Stephen Ferguson ◽  
Hongbing Wang
Keyword(s):  
Constitutive Androstane Receptor ◽  
Human Hepatocytes ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes

scholarly journals Role of the Constitutive Androstane Receptor in Xenobiotic-Induced Thyroid Hormone Metabolism

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 995-1002 ◽  
Author(s):  
Mohammed Qatanani ◽  
Jun Zhang ◽  
David D. Moore
Keyword(s):  
Cell Proliferation ◽  
Thyroid Hormone ◽  
Constitutive Androstane Receptor ◽  
Follicular Cell ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Thyroid Follicular Cell ◽  
Serum Tsh ◽  
Tsh Levels

The induction of hepatic drug metabolizing enzymes alters not only the metabolism of the xenobiotic substances that induce them but also the metabolism of various endogenous hormones. The xenobiotic receptor constitutive androstane receptor (CAR) (NR1I3) mediates the well-studied induction of CYP2B genes and other drug-metabolizing enzymes by phenobarbital (PB), an antiepileptic drug that has been shown to alter thyroid hormone (TH) levels. Here we show that CAR is required for PB-mediated disruption of TH homeostasis and the induction of thyroid follicular cell proliferation. Treatment with PB or the more potent and more effective CAR ligand 1, 4-bis-[2-(3, 5,-dichloropyridyloxy)] benzene resulted in universal induction of thyroid hormone glucuronidation and sulfation pathways in a CAR-dependent manner. This resulted in a decrease in serum T4 concentration and a concomitant increase in serum TSH levels. CAR activation also decreased serum T3 levels in mice in which T3 production was blocked. The increase in serum TSH levels resulted in the stimulation of thyroid-follicular cell proliferation. These results highlight the central role of the xenosensor CAR in drug-hormone interactions.

Role of Citrus Limonoid as a Possible Bioavailability Enhancer

2020 ◽  
Vol 859 ◽  
pp. 132-138
Author(s):  
Nusara Piyapolrungroj ◽  
Panadda Phattanawasin ◽  
Uthai Sotanaphun ◽  
May Phyu Thein Maw
Keyword(s):  
Drug Absorption ◽  
Oral Delivery ◽  
The Body ◽  
Drug Metabolizing Enzymes ◽  
Dependent Manner ◽  
Drug Bioavailability ◽  
Concentration Dependent Manner ◽  
Metabolizing Enzymes ◽  
Calcein Am

The oral delivery is the most practical route to deliver drugs into the body, however drug-metabolizing enzymes and drug transporters can play important roles in modulating drug absorption. This study intended to find a natural bioenhancer for improving drug bioavailability. Two limonoids, including limonin deepoxy and nomilin, isolated from pomelo pulp were studied and the inhibition effects on human CYP3A4 and P-gp were investigated. Testosterone 6β-hydroxylation was performed in recombinant human CYP3A4 to discover the effects on CYP activity. Daunorubicin transport in Caco-2 and calcein-AM uptake in LLC-PK1 and LLC-GA5-COL300 were conducted to evaluate the effects on P-gp function. The results show that both limonin deepoxy and nomilin could inhibit CYP3A4 and only nomilin exhibited mechanism-based inhibition. Nomilin was able to inhibit human P-gp in the concentration-dependent manner. Taken together, nomilin demonstrated strong activities on both CYP3A4 and P-gp, indicating that nomilin could possibly be used as a bioavailability enhancer.

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